Ge Yang, van Roon Lieke, van Gils Janine M, Geestman Tom, van Munsteren Conny J, Smits Anke M, Goumans Marie José T H, DeRuiter Marco C, Jongbloed Monique R M
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, Netherlands.
Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands.
Front Cardiovasc Med. 2022 Oct 6;9:758265. doi: 10.3389/fcvm.2022.758265. eCollection 2022.
A role for cardiac sympathetic hyperinnervation in arrhythmogenesis after myocardial infarction (MI) has increasingly been recognized. In humans and mice, the heart receives cervical as well as thoracic sympathetic contributions. In mice, superior cervical ganglia (SCG) have been shown to contribute significantly to myocardial sympathetic innervation of the left ventricular anterior wall. Of interest, the SCG is situated adjacent to the carotid body (CB), a small organ involved in oxygen and metabolic sensing. We investigated the remodeling of murine SCG and CB over time after MI. Murine SCG were isolated from control mice, as well as 24 h, 3 days, 7 days and 6 weeks after MI. SCG and CBs were stained for the autonomic nervous system markers β3-tubulin, tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT), as well as for the neurotrophic factors brain derived neurotropic factor (BDNF), nerve growth factor (NGF) and their tyrosine receptor kinase (pan TRK). Results show that after MI a significant increase in neuron size occurs, especially in the region bordering the CB. Co-expression of TH and ChAT is observed in SCG neuronal cells, but not in the CB. After MI, a significant decrease in ChAT intensity occurs, which negatively correlated with the increased cell size. In addition, an increase of BDNF and NGF at protein and mRNA levels was observed in both the CB and SCG. This upregulation of neurotropic factors coincides with the upregulation of their receptor within the SCG. These findings were concomitant with an increase in GAP43 expression in the SCG, which is known to contribute to axonal outgrowth and elongation. In conclusion, neuronal remodeling toward an increased adrenergic phenotype occurs in the SCG, which is possibly mediated by the CB and might contribute to pathological hyperinnervation after MI.
心肌梗死后心脏交感神经超支配在心律失常发生中的作用已得到越来越多的认识。在人类和小鼠中,心脏接受来自颈部和胸部的交感神经支配。在小鼠中,颈上神经节(SCG)已被证明证明对左心室前壁心肌交感神经支配作出显著贡献。有趣的是,颈上神经节位于颈动脉体(CB)附近,颈动脉体是一个参与氧气和代谢感知的小器官。我们研究了心肌梗死后小鼠颈上神经节和颈动脉体随时间的重塑情况。从对照小鼠以及心肌梗死后24小时、3天、7天和6周的小鼠中分离出颈上神经节。对颈上神经节和颈动脉体进行自主神经系统标志物β3-微管蛋白、酪氨酸羟化酶(TH)和胆碱乙酰转移酶(ChAT)染色,以及对神经营养因子脑源性神经营养因子(BDNF)、神经生长因子(NGF)及其酪氨酸受体激酶(泛TRK)染色。结果表明,心肌梗死后神经元大小显著增加,尤其是在与颈动脉体接壤的区域。在颈上神经节神经元细胞中观察到TH和ChAT的共表达,但在颈动脉体中未观察到。心肌梗死后,ChAT强度显著降低,这与细胞大小增加呈负相关。此外,在颈动脉体和颈上神经节中均观察到BDNF和NGF在蛋白质和mRNA水平上的增加。神经营养因子的这种上调与它们在颈上神经节内受体的上调相吻合。这些发现与颈上神经节中GAP43表达的增加同时出现,已知GAP43有助于轴突生长和延长。总之,颈上神经节发生了向肾上腺素能表型增加的神经元重塑,这可能由颈动脉体介导,并可能导致心肌梗死后的病理性超支配。
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